ArticleProceedings of the National Academy of Sciences of the United States of America2011
Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 159 papers, 2 of them syntheses that pooled it.
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Who cites it
159 citing papers in PubMed, 2 syntheses or guidelines pooled it, 322 citations in OpenAlex.
- The impact of maternal nutrition on offspring's risk of non-communicable diseases in adulthood: a systematic review.Journal of global health · 2019Pooled it
- Genome-wide meta-analysis of genetic susceptible genes for Type 2 Diabetes.BMC systems biology · 2012Pooled it
- Epigenetics and childhood obesity: DNA methylation coordinates environment and gene regulation.Endocrine reviews · 2026Review
- The Impact of Maternal Obesity and Diabetes on the Development of Congenital Heart Defects (CHDs) in Offspring: A Narrative Review.Metabolites · 2026Review
- Phenotype of insulin-dependent diabetes in chronic undernutrition: beta cell stress and immune dysfunction-a rural sub-Saharan perspective on type 5 diabetes.Diabetologia · 2025Review
- Epigenetic memory as crucial contributing factor in directing the differentiation of human iPSC into pancreatic β-cells in vitro.Cell and tissue research · 2025Review
- Evolving Characteristics of Type 2 Diabetes Mellitus in East Asia.Endocrinology and metabolism (Seoul, Korea) · 2025Review
- Decoding the Influence of Obesity on Prostate Cancer and Its Transgenerational Impact.Nutrients · 2023Review
- Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood.Journal of the American Heart Association · 2023Article
- Biomarkers of aging.Science China. Life sciences · 2023Review
- Variation in DNA Methylation in Avian Nestlings Is Largely Determined by Genetic Effects.Molecular biology and evolution · 2023Article
- Towards a better understanding of diabetes mellitus using organoid models.Nature reviews. Endocrinology · 2023Review
- Epigenetic modulation of cell fate during pancreas development.Trends in developmental biology · 2023Article
- Type 1 diabetes mellitus in the context of high levels of rural deprivation: differences in demographic and anthropometric characteristics between urban and rural cases in NW Ethiopia.Frontiers in clinical diabetes and healthcare · 2023Article
- The transcription factor HNF-4α: a key player in haematological disorders.Archives of medical science : AMS · 2023Article
- Current Knowledge on the Pathophysiology of Lean/Normal-Weight Type 2 Diabetes.International journal of molecular sciences · 2022Review
- The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities.IBRO neuroscience reports · 2022Review
- Article
- Development and the art of nutritional maintenance.The British journal of nutrition · 2022Review
- Human Milk Lipids Induce Important Metabolic and Epigenetic Changes in Neonates.Clinics in perinatology · 2022Review
99 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 7 institutions in 4 countries.
Funding
Abstract
Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.
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